Effects of low doses of esmolol on cardiac and vascular function in experimental septic shock

Abstract

Background: Administration of a selective β1-blocker, such as esmolol, in human septic shock has demonstrated cardiovascular protective effects related to heart rate reduction. Certain experimental data also indicate that esmolol exerts systemic anti-inflammatory and beneficial effects on vascular tone. Thus, the present study aimed to determine whether a non-chronotropic dose of esmolol maintains its protective cardiovascular and anti-inflammatory effects in experimental septic shock. Methods: Four hours after cecal ligation and puncture (CLP), Wistar male rats were randomly allocated to the following groups (n = 8): CLP, CLP + E-1 (esmolol: 1 mg.kg). An additional eight rats underwent sham operation. All rats received a continuous infusion of saline, analgesic and antibiotics 4 hours after the surgery. Assessment at 18 hours included in vivo cardiac function assessed by echocardiography and ex vivo vasoreactivity assessed by myography. Circulating cytokine levels (IL-6 and IL-10) were measured by ELISA. Cardiac and vascular protein expressions of p-NF-κB, IκBα, iNOS, p-AKT/AKT and p-eNOS/eNOS were assessed by western blotting. Results: CLP induced tachycardia, hypotension, cardiac output reduction, hyperlactatemia and vascular hyporesponsiveness to vasopressors. Compared to CLP animals, heart rate was unchanged in CLP + E-1 and CLP + E-5 but was reduced in CLP + E-18. Stroke volume, cardiac output, mean arterial pressure and lactatemia were improved in CLP + E-1 and CLP + E-5, while vascular responsiveness to phenylephrine was only improved in CLP + E-5 and CLP + E-18. Plasma IL-6 levels were decreased in all esmolol groups. p-NF-κB was decreased in both cardiac and vascular tissues in CLP + E-5 and CLP + E-18. Conclusion: In experimental septic shock, low doses of esmolol still improved cardiac function and vasoreactivity. These benefits appear to be associated with a modulation of inflammatory pathways.

The β1-Adrenergic Receptor Contributes to Sepsis-Induced Immunosuppression Through Modulation of Regulatory T-Cell Inhibitory Function*

“…Beside this immune rebalancing in experimental mid-grade sepsis, it is important to reiterate that β 1 -AR blockade also has major cardiovascular effects. In agreement with most other experimental or clinical studies, septic mice receiving β-AR blockade showed no alteration in cardiac power, despite a decrease in HR, suggesting improved cardiac efficiency (10, 15, 44, 50). However, it should be borne in mind that animals only received an initial subcutaneous bolus of fluid resuscitation and no fluids nor catecholamines thereafter.…”

“…In numerous conditions, such as acute heart failure, burn injuries, and septic shock, β 1 -AR blockade has been consistently associated with protective effects on inflammation and hemodynamics (15, 42, 43). As others, we too found a global decrease in pro- and anti-inflammatory mediators in animals with mid-grade sepsis treated by β 1 -AR blockade (15, 44, 45). Underlying mechanisms are still not elucidated.…”

“…Relatively few experimental and, in particular, clinical studies have investigated the inflammatory effects of β 1 -AR blockade in sepsis. These studies report a global decrease in both pro-and anti-inflammatory circulating cytokines although have not delved into underlying mechanisms (14)(15)(16)(17). Little is also known about the effects of β 1 -AR blockade on the early adaptive immune response (18,19).…”

“…Initial single-center studies in human septic shock have mainly reported hemodynamic benefits with improvements in cardiac efficiency and, in one study, a survival benefit (8)(9)(10). Premorbid β 1 -blocker exposure is also associated with a decrease in ICU mortality (11)(12)(13) which may relate to their immunomodulatory actions (14)(15)(16).…”

An exploration of the protective mechanism of esmolol on the heart of septic rats based on the beta-adrenergic signaling pathway.

“…Esmolol, as an ultra-short-acting selective β 1 receptor blocker, has been confirmed, at home and abroad, to have cardiac protective effect, and to reduce the hospitalization rate and mortality of septic patients with cardiac dysfunction [18] [19]. The results of animal experiments also confirmed that it could reverse left ventricular hypertrophy [20].…”